title: Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor.
abstract: Antagonizing the human M3 muscarinic receptor (hM3R) over a long time is a key feature of modern bronchodilating COPD drugs aiming at symptom relief. The long duration of action of the antimuscarinic drug tiotropium and its kinetic subtype selectivity over hM2R are investigated by kinetic mapping of the binding site and the exit channel of hM3R. Hence, dissociation experiments have been performed with a set of molecular matched pairs of tiotropium on a large variety of mutated variants of hM3R. The exceedingly long half-life of tiotropium (of more than 24 h) is attributed to interactions in the binding site; particularly a highly directed interaction of the ligands' hydroxy group with an asparagine (N508(6.52)) prevents rapid dissociation via a snap-lock mechanism. The kinetic selectivity over hM2R, however, is caused by differences in the electrostatics and in the flexibility of the extracellular vestibule. Extensive molecular dynamics simulations (several microseconds) support experimental results.
authors.affiliation: Lead Identification and Optimization Support, ‡Respiratory Diseases Research, and §Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG , Birkendorfer Straße 65, 88397 Biberach, Germany.
authors.forename: Christofer S
authors.initials: CS
authors.lastname: Tautermann
authors.forename: Tobias
authors.initials: T
authors.lastname: Kiechle
authors.forename: Daniel
authors.initials: D
authors.lastname: Seeliger
authors.forename: Sonja
authors.initials: S
authors.lastname: Diehl
authors.forename: Eva
authors.initials: E
authors.lastname: Wex
authors.forename: Rolf
authors.initials: R
authors.lastname: Banholzer
authors.forename: Florian
authors.initials: F
authors.lastname: Gantner
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pieper
authors.forename: Paola
authors.initials: P
authors.lastname: Casarosa
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009154:Mutation; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000069447:Tiotropium Bromide
chemical_list: D043587:Receptor, Muscarinic M3; D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide